PROJECT SUMMARY/ABSTRACT I am a young neuroscientist with Ph.D. training from the University of Washington and postdoctoral training from the University of California, San Francisco. I have acquired solid knowledge in the principles of neuroscience and excellent technical expertise on neuronal signaling pathways and pharmacology in prion disease. My long-term career goals are to establish a research laboratory focusing on understanding and developing therapeutics against prion and Alzheimer's diseases as an independent investigator. In addition, I expect to teach and train health professionals and neuroscientists. To attain these goals, I intend to dedicate the 5 years award period to expand my scientific knowledge and expertise on research skills. The scientific activities of this proposal will include participating in seminars, journal clubs, national and international scientific meetings, preparing manuscripts for publications, and lab management. The research activities will include learning neuropathological analysis of prion and Alzheimer's diseases. Also, during the award period, I will learn techniques of immunohistochemistry and imaging, and get more hands-on experience on the convection enhanced delivery of gene products to the mouse brain for gene therapy against prion disease. Prion disease is one of the most devastating neurodegenerative diseases. Unlike other neurodegenerative diseases, it is caused by a single pathogen, pathogenic prion (PrPSc), which is converted from normal cellular prion (PrPC). However, physiological roles of PrPC and signaling pathways involved in prion disease are poorly understood. Identification of key molecules and pathways in prion disease will facilitate to develop early diagnosis and therapeutics targeting prion disease. Recent studies from our laboratory and others show that PrPC may play a role in amyloid precursor protein (APP) pathways. In this proposal, I will utilize a brain aggregate culture system, which represents the in vivo system most effectively. The benefits of using brain aggregates are reducing animal numbers for experiments, reducing numbers of days for experiments, and utilizing various aggregate cultures from transgenic mice. This project seeks i) to determine pathways or factors important in prion disease and ii) to develop therapeutics against prion disease using the multi- therapeutic approaches, based on its mechanisms. Elucidating pathways involved in prion disease may allow us not only to develop therapeutics, but also to identify factors for early diagnosis. As a long term goal, we hope to i) link pathological processes within neurodegenerative diseases, ii) shed light on the cellular processes that may be applicable to other neurodegenerative disorders and iii) develop therapeutics for neurodegenerative disorders.